PPG OVERALL Abstract: Neuropsychiatric lupus (NPSLE) is a common and debilitating manifestation of Systemic Lupus Erythematosus (SLE). For over a decade, we have been studying the contribution of a subset of anti-DNA antibodies that cross reacts with the N-methyl D-aspartate receptor, termed DNRAb, to cognitive impairment in NPSLE, and to impairments in fetal health of DNRAb+ mothers. We have developed a mouse model in which we have now shown that DNRAb, when they penetrate the hippocampus, cause acute neuronal death subsequently leading to persistent microglial activation, neuronal dendritic loss, and cognitive impairments. Suppression of microglial activation by angiotensin converting enzyme (ACE) inhibitors leads to a restoration of neuronal integrity and cognitive function. Using the same model, we have demonstrated that maternal DNRAb cause death of female fetuses and cognitive impairment in male offspring through transplacental transport. We have demonstrated in subjects with SLE that memory impairment is associated with increased titers of DNRAb and that a reduced microstructural integrity of parahippocampal fibers also associates with DNRAb. We proposed to continue to study both the mouse model and SLE patients, to understand the mechanisms of microglial activation and how ACE inhibitors restore neuronal integrity. We will determine how DNAbs alter male and female fetal brain development. We will assess microglial activation and loss of blood brain barrier integrity in SLE patients and the association of these abnormalities with elevated titers of DNRAb. These studies have already led to a funded clinical trial of ACE inhibitors in non-focal central nervous system manifestations of NPSLE, and have the potential to reveal additional potential therapeutic strategies.